Pyranones

ABSTRACT

A process for the separation of at least one isomer from a mixture of isomers of a tetrahydropyran-2-one, having at least two chiral centers which comprises selective reaction of at least one isomer with a reagent catalyzed by a hydrolase enzyme whereby at least one isomer is preferentially converted into a distinct chemical species from the other isomers so that it is susceptible of separation by an appropriate chemical or physical separation process in which the tetrahydropyran-2-one is of Formula (1): ##STR1## wherein: Z is --H or a protecting group susceptible of reaction with the reagent under the influence of the enzyme; and 
     Y is formyl or protected formyl.

This is a 371 of PCT/GB92/01666 filed Sep. 11, 1992 and a divisionalapplication of U.S. Ser. No. 07/946,194, filed Sep. 17, 1992, now U.S.Pat. No. 5,443,971.

This invention relates to processes for the preparation oftetrahydropyran-2-ones which involve a kinetic resolution stage forproducing at least one optically active isomer of a tetrahydropyran-2-one having at least two chiral centres from a mixture ofisomers, such as a cis or trans racemate or a mixture of cis and transracemates, to certain novel isomers, particularly single enantiomers, ofthe tetrahydropyran-2-one, and to certain novel dihydropyran-2-ones andpyran-2-ones.

Optically active materials such as tetrahydropyran-2-ones may be used asintermediates in the manufacture of compounds such as pharmaceuticals,agrochemicals and chemicals for use in electronics industry. Theoptically active tetrahydropyran-2-ones of the present invention areparticularly useful as intermediates in the manufacture of HMG-CoAreductase inhibitors. Available processes for the production oftetrahydropyran-2-ones are typically lengthy, require reagents which areexpensive or difficult to handle on a large scale, give poor overallyields, and do not give access to all optical isomers.

According to the present invention there is provided a process for theseparation of at least one isomer from a mixture of isomers of atetrahydropyran-2-one, having at least two chiral centres, whichcomprises selective reaction of at least one isomer with a reagentcatalysed by a hydrolase enzyme whereby at least one isomer ispreferentially converted into a distinct chemical species from the otherisomers so that it is susceptible of separation by an appropriatechemical or physical separation process in which thetetrahydropyran-2-one is of Formula (1): ##STR2## wherein: Z is --H or aprotecting group susceptible of reaction with the reagent under theinfluence of the enzyme; and

Y is formyl or protected formyl.

The protecting group, Z, is preferably a readily displaceable protectinggroup. Examples of suitable readily displaceable protecting groupsinclude --PO.(OR³)₂, --CO.R³ ; --SO.OR³ ; --NO₂ and --(CO).OR³ in whicheach R³ is independently optionally substituted alkyl, optionallysubstituted alkenyl or optionally substituted phenyl. Preferred examplesof the protecting group, Z, include benzoyl, --COCH₃, --CO(n--C₃ H₇) and--(CO)OCH₃.

Where the group represented by Y is protected formyl it is preferably ofthe formula --CH(OR)₂, --CH(SR)₂ or --CH(OR)(SR) wherein each Rindependently is --H, optionally substituted alkyl, optionallysubstituted alkenyl or optionally substituted phenyl or two groups --ORor --SR attached to the same carbon atom, together with the carbon atomto which they are attached, form a 5- to 7-membered heterocycle.Examples of such groups are: ##STR3## in which each T is a divalentgroup. Examples of suitable groups represented by T are --C₂ H₄ --,--(CH₂)₃ --, --CH(CH₃)--CH(CH₃)-- and --CH(Ph)--CH(Ph)--. Alternatively,the formyl group may be protected by conversion into an oxazolidine,imidazolidine, thiazolidine, bisulphite, O-substituted cyanohydrin suchas O-acyl, O-tetrahydropyran-2-yl and O--SiR³ in which R³ is ashereinbefore defined, cyanohydrin, hydrazone or oxime derivative. It ispreferred that the formyl group is protected by conversion into anoxazolidine.

Where R or R³ is or contains an alkyl group this is preferably C₁₋₁₂-alkyl, more preferably C₁₋₆ -alkyl and especially methyl, ethyl, propylor butyl.

Where R or R³ is or contains an alkenyl group this is preferably C₂₋₁₂-alkenyl, more preferably C₂₋₆ -alkenyl and especially vinyl. Where anyR or R³ is alkyl or alkenyl it may be in the form of a straight or R³branched chain.

Where the group represented by R or is optionally R³ is optionallysubstituted alkyl or alkenyl, the substituent is preferably selectedfrom C₁₋₆ -alkoxy; halogen, such as --Cl, --Br or --F; hydroxy; cyano;--NR₂ in which R is as hereinbefore defined such as --NMe₂ ; cyclohexyl;phenyl; and protected primary and secondary amino groups such as--NHCOMe and --N(SiMe₃)₂. Where the group represented by R or R³ isoptionally substituted phenyl, the substituent is preferably selectedfrom C₁₋₆ -alkyl, especially methyl; C₁₋₆ -alkoxy, especially methoxy;cyclohexyl; phenyl; nitro; hydroxy; cyano; halogen, especially Cl, Br,or F; --NR₂ in which R is as hereinbefore defined such as --NMe₂ ; andprotected primary and secondary amino groups such as --NHCOMe and--N(SiMe₃)₂.

Examples of particularly preferred groups represented by Y are CO.H,--CH(OCH₃)₂, --CH(OPh)₂, --CH(OC₂ H₅)₂, --CH(SC₂ H₅)₂, --CH(OC₂ H₅)(SC₂H₅), ##STR4## or a formyl group protected by formation of an oxazolidinewith ethanolamine or by formation of an imidazolidine by reaction with1,2-ethylenediamine, or by formation of a thiazolidine by reaction witha 2-aminoethanethiol.

The enzyme catalysed reaction is a kinetic resolution which means thatthe reaction occurs because the enzyme catalyses the reaction of thereagent with different isomers at different rates. A compound with twochiral centres may consist of a mixture of four isomers i.e. two pairsof enantiomers, and a suitable enzyme catalyses reaction of the reagentwith each isomer at a different rate so that over a period of time thecomposition changes from a mixture of, for example 4 isomers to amixture of 3 isomers and a more distinct chemical species which can beseparated from the unchanged isomers by appropriate conventionalseparation techniques; or one enantiomer of an enantiomer pair issimilarly changed to a distinct chemical species which may be similarlyseparated.

The nature of the reagent and the enzyme depends upon the nature of thegroup --OZ and the stereochemistry of the isomer(s) with which thereagent is to react. Where Z is --H the selective reaction isconveniently a trans-esterification or esterification and the reagent isan ester or acid capable of reaction with the group --OH when catalysedby the enzyme. In this process the group --OH in the selected isomer(s)is converted into an ester so that the isomer(s) is/are chemicallydistinct and can be readily separated from the other isomer(s) in whichZ is still --H. In this reaction, the enzyme preferably causes the groupR⁴ CO-- of an ester, R⁴ COOR⁵ or an acid R⁴ COOH (in which R⁴ and R⁵each independently is optionally substituted alkyl, alkenyl or aryl) toreact preferentially with a group --OZ in one, or all except one, isomerin the mixture. It is preferred that the R⁴ CO-- portion ispreferentially attacked by the group 4 --OH in one, or all except one,of the isomers in the mixture.

The alkyl and alkenyl groups represented by R⁴ and R⁵ are preferablyC₁₋₁₈ -alkyl and C₂₋₁₈ -alkenyl, more preferably C₁₋₆ -alkyl and C₂₋₅-alkenyl, especially C₁₋₄ -alkyl and vinyl and allyl respectively andmay be straight or branched chain alkyl. The aryl groups represented byR⁴ and R⁵ are preferably phenyl or naphthyl each of which may beoptionally substituted. Where the groups R⁴ and R⁵ are optionallysubstituted the substituent may be selected from any of those describedabove for R. R⁵ is preferably an alkenyl group, more preferably a C₂₋₃-alkenyl group and especially vinyl. R⁴ is preferably an alkyl group,more preferably a C₁₋₄ -alkyl group and especially methyl, ethyl orn-propyl. The ester of the formula R⁴ COOR⁵ may be an alkyl ester, e.g.an alkyl alkanoate, such as methyl acetate, methyl butyrate or ethylacetate or an alkyl benzoate, such as methyl benzoate, but is preferablya non-reversible acyl donor, especially an alkenyl ester, morepreferably an alkenyl alkanoate such as vinyl acetate or vinyl butyrate.

Scheme 1 illustrates a trans-esterification process where the reagent isR⁴ COOR⁵ or an esterification process whre the reagent is R⁴ COOH for amixture of isomers of Formula (1) in which Z is --H and Y is ashereinbefore defined:

Scheme 1 ##STR5##

In Scheme 1, Compounds 1B, 1C & 1D are isomeric esters formed bypreferential esterification of the corresponding alcohol isomers in themixed isomer starting material and are distinct chemical species fromthe unchanged alcohol, Compound 1A. The latter may be separated from theformer by any convenient means such as chromatography, solventextraction, crystallisation or distillation.

The trans-esterification and esterification reactions may be performedin a two phase liquid medium comprising water and an immiscible organicliquid. Where two phases are present the enzyme partitions predominantlyinto the aqueous phase and thus the enzyme catalysed reaction occursmainly in the aqueous phase. In the aqueous phase the equilibriumposition of the trans-esterification and esterification reactions may beshifted resulting in a decreased yield of the required product. Thus,the trans-esterification or esterification reaction is preferablyperformed in a single phase organic liquid medium which contains smallamounts of water.

By small amounts of water it is meant that water immiscible organicliquids contain less than or equal to the amount of water required tosaturate the organic liquid and water miscible organic liquids containless than 50%, preferably less than 20% and especially less than 10%water.

When water is present in predominantly organic systems the concentrationof water may not be very meaningful and the system may be better definedusing the thermodynamic activity of water (Aw). Aw values may bemeasured via relative humidity in an equilibrated gas phase as describedin EP 64855A. Water under standard state conditions has by definition anAw value of 1. For the trans-esterification reaction the activity ofwater (Aw) in the organic liquid is less than 1 and greater than 0.05,preferably from 0.95 to 0.1.

The reaction medium may comprise one or more of the participatingspecies, such as the tetrahydropyran-2-one or the ester R⁴ COOR⁵ or theacid R⁴ COOH or a substantially inert organic liquid or a mixture ofsuch liqiuds. Suitable inert organic liquids include a straight orbranched chain alkane, especially a C₅₋₁₆ -alkane such as hexadecane,iso-octane or hexane; an optionally substituted arene, especially anoptionally substituted benzene such as toluene or xylene; an optionallysubstituted ether, especially a C₁₋₅ -alkoxy-C₁₋₅ -alkane such ast-butoxymethane or ethoxyethane; a C₄₋₈ -cyclic ether such astetrahydrofuran or 1,4-dioxane; a halogenated alkane, especially ahalogenated C₁₋₃ -alkane such as dichloromethane, trichloromethane,tetrachloromethane or 1,1,2-trichloroethane; a carboxylic acid,especially a C₁₋₃ -carboxylic acid such as ethanoic or propanoic acid;an alkyl cyanide, especially a C₁₋₃ -alkylcyanide such as acetonitrile;an alkyl alkanoate, especially a C₁₋₅ -alkyl C₁₋₅ -alkanoate such asi-propyl acetate, methyl butyrate or ethyl acetate; an alkyl benzoate,especially a C₁₋₅ -alkyl benzoate, such as methyl benzoate or ethylbenzoate; an alkenyl alkanoate, especially a C₂₋₅ -alkenyl C₁₋₅-alkanoate such as vinyl acetate or vinyl butyrate; or an optionallybranched alkanol, especially a C₁₋₁₀ -alkanol, and more especially aC₁₋₆ -alkanol, such as butan-1-ol, butan-2-ol, t-butanol, propan-2-ol,ethanol or methanol.

Where Z is a protecting group the selective reaction is conveniently ahydrolysis and the reagent is a hydrolytic agent, such as water or analkanol, ROH in which R is as hereinbefore defined, which is capable ofreplacing the protecting group Z by H when catalysed by the enzyme. Inthis process the group OZ in the selected isomer(s) is converted into anOH group so that the selected isomer(s) is/are chemically distinct andcan be readily separated from the other isomer(s) in which Z is still aprotecting group. In this reaction the enzyme preferably catalyses thehydrolysis of one or more isomers in a mixture of isomers of Formula (1)in which Z is a protecting group, such as --CO.R⁴ Scheme 2 illustratesthe hydrolysis of a mixture of isomeric esters of Formula (1) in which Zis --CO.R⁴ and R⁴ and Y are as hereinbefore defined:

Scheme 2 ##STR6##

In Scheme 2, Compounds 1F, 1G and 1H are alcohols formed by preferentialhydrolysis of the corresponding esters in the starting material andthese are distinct chemical species from the unchanged ester, Compound1E. The former may be separated from the latter by any convenient meanssuch as chromatography, solvent extraction, crystallisation ordistillation. Once separated Compound 1E may be chemically hydrolysed tothe corresponding hydroxy compound.

The enzymatic hydrolysis reaction may be performed in a liquid mediumsuch as water, an organic liquid or a mixture thereof. Suitable organicliquids for the hydrolysis are those described above for thetrans-esterification. Where the liquid medium comprises water or analkanol, the water or alkanol may form only a proportion of the liquidmedium, e.g. from 1% to 50% thereof, depending on the equilibriumconstant for the system, and may be buffered at a pH from 4 to 10,preferably from 4 to 9 and especially from 6 to 8. The buffer may beinorganic or organic and is preferably an inorganic phosphate such assodium or potassium phosphate or an organic amine salt, such as thehydrochloride, acetate, phosphate or benzoate salt oftri(hydroxymethylamino)methane.

The reaction medium for the trans-esterification, esterification or thehydrolysis may further comprise components which stabilise the enzymeand maximise its catalytic efficiency. Such components may comprisecations, especially H⁺ and H₃ O⁺ ; alkali metal cations such as Li⁺, Na⁺and K⁺ ; alkaline earth cations such as Mg²⁺ and Ca²⁺, Group III metalcations such as Al³⁺ ; transition metal cations such as Zn²⁺, Fe²⁺,Cu²⁺, Co²⁺ and Ni²⁺ ; and/or ammonium and substituted ammonium cationssuch as NR₄ ⁺ in which each R independently is as hereinbefore defined.Other suitable components may comprise anions, especially halides suchas F⁻, Cl⁻, Br⁻ and I⁻ ; oxyphosphorus anions such as HPO₄ ²⁻ and PO₄ ³⁻; oxysulphur anions such as SO₄ ²⁻ ; oxynitrogen anions such as NO₃ ⁻ ;OH⁻ ; CO₃ ²⁻ and/or organic anions such as formate, acetate, oxalate,tartrate, malonate or succinate. The preferred cations and anions may beused in combination or as salts with other anions and cations,respectively. Salts containing these ions may be employed undissolved inthe reaction medium in order to change the state of hydration and thusthe activity of water in the medium. For example when sodium carbonatedecahydrate is added to the reaction medium it becomes sodium carbonatemonohydrate by losing 9 equivalents of water, in this way a known amountof water may be added to the reaction medium.

To this end the salts may be hydrated salts or mixtures of anhydrous andhydrated salts (see Biochim, Biophys Acta (1991) 1078, 326). Thehydrolysis medium may also contain antioxidants such as ascorbates orthiols, such as dithiothreitol, 2,3-dimethylpropanethiol, ethanethioland cysteine.

The trans-esterification, esterification and hydrolysis reactions may beperformed at temperatures from 0° C. to 100° C., preferably from 10° C.to 60° C. more preferably from 25° C. to 60° C. and especially from 30°C. to 60° C. During the course of the hydrolysis reaction an inorganicbase, preferably an alkali metal hydroxide such as sodium hydroxide, maybe added to maintain the pH of the reaction mixture. The reaction mediummay be agitated by appropriate methods such as stirring, shaking orsonicating.

The hydrolase enzyme is preferably an esterase, lipase, nitrilase,amidase, peptidase, glycosidase or phosphatase derived from microbial,animal or plant sources. Especially preferred enzymes areChromobacterium viscosum lipase from Biocatalysts Ltd, AMANO P lipasefrom Amano Pharmaceuticals (AMANO is a trade mark of AmanoPharmaceuticals), Pseudomonas fluorescens lipase from Biocatalysts orFluka Chemie AG, Mucor miehi strain such as NOVO IM60 and NOVO lypozymefrom Novo Industrie (NOVO is a trade mark of Novo Industrie) orLipoprotein lipase from Pseudomonas species, from Boehringer MannheimGmbH or Fluka Chemie AG.

Suitable forms are microbial whole cell preparations or fractionsderived from microbial, plant and animal tissues containing the requiredhydrolase activities. Such fractions include secreted enzymes, brokencells, cell-free extracts and purified hydrolase enzymes. The hydrolaseenzyme may be prepared and used in the reaction as a lyophilised solidor water-containing liquid. When the hydrolase enzyme is prepared as alyophilised solid it may further comprise components to stabilise theenzyme system and maximise its catalytic activity and antioxidants asdescribed above.

The lyophilised solid may further comprise organic additives such assugars, preferably glucose, mannose or trehalose; or polyols such aspolyethyleneglycol; or detergents such as alkylammonium salts oralkylsulphonate salts. The hydrolase enzyme may be coated, for exampleby passive adsorption onto an inorganic or organic support material orcovalently bonded onto an inorganic or organic support material. Theinorganic support material may be a powdered or beaded silicate; aninfusorial material, such as diatomaceous earth; zeolite;montmorillonite clay; or finely divided carbon such as charcoal or apolyphosphazene. A preferred inorganic support material is a beadedglass, sand, silica gel; a diatomaceous earth such as CELITE (CELITE isa trade mark of Johns Manville Corporation); a molecular sieve (e.g.4A); or charcoal. A convenient organic support is a resin such asEUPERGIT C (EUPERGIT is a trade mark of Rohm Pharma); an ionic exchangeresin; a polysaccharide; a polyacrylamide; a protein; a nucleic acid; alipid; a detergent capable of forming micelles; or a liposome. Apreferred organic support material is an anionic exchange resin or acellulosic material such as SEPHAROSE (SEPHAROSE is a trade mark ofPharmacia, Sweden).

The hydrolase enzyme may be prepared for use in the hydrolysis reactionas a stock solution in an aqueous liquid medium containing componentswhich stabilise, maximise its catalytic activity and prevent itsoxidation as described above. The same stock solution may be freezedried at a temperature from -70° C. under vacuum until almost dry togive a hydrolase enzyme residue which is suitable for use in thetrans-esterification or esterification reactions. However, it isimportant that the reaction medium for the trans-esterification andesterification reactions contains at least some water otherwise thehydrolase enzyme is ineffective as a trans-esterification oresterification catalyst. Thus either the enzyme residue must containsome water of water must be added to the trans-esterification oresterification medium.

A compound of Formula (1) in which Y is protected formyl such as--CH(OR³)₂ may be prepared a) by reaction of the corresponding compoundin which Y is --CHO with an alcohol, R³ OH in which R³ is ashereinbefore defined, in the presence of dry hydrogen chloride or b) byreaction of a compound of Formula (1) in which Y is --CHX₂ with R³ OH inthe presence of a silver salt such as silver nitrate. A compound ofFormula (1) in which Y is protected formyl such as --CH(SR³)₂ may beprepared by reaction of the corresponding compound in which Y is --CHOwith a thiol, R³ SH in which R³ is as hereinbefore defined, in thepresence of BF₃.Et₂ O. A compound of Formula (1) in which Y is protectedformyl such as --CH(OR³)(SR³) may be prepared by reaction of thecorresponding compound in which Y is --CHO with a mixture of alcohol, R³OH and thiol R³ SH in which R³ is as hereinbefore defined.

Compounds of Formula (1) in which Y is protected formyl such as--CH(OR³)₂, --CH(SR³)₂ or --CH(OR³)(SR³) in which the R³ groups arejoined to form a 5- to 7-membered heterocycle may be formed by reactionof the corresponding compound of Formula (1) in which Y is --CHO with adiol such as ethan-1,2-diol, a dithiol such as propan-1,3-dithiol or ahydroxythiol such as 2-hydroxyethanethiol. A compound of Formula (1) inwhich Y is oxazolidinyl, imidazolidinyl or thiazolidinyl, i.e. aprotected formyl group, may be prepared by reaction of the correspondingcompound of Formula (1) in which Y is --CO.H or --CHX₂ (in which X ishalogen) with a 1-hydroxy-2-amino alkane such as an ethanolamine, or a1,2-diamino alkane such as an ethylenediamine, or a1-thiol-2-aminoalkane such as an aminoethanethiol, respectively. Wherethe formyl group is protected by conversion into a bisulphite,cyanohydrin, an O-substituted cyanohydrin, hydrazone or oxime derivativethese may be formed by reaction of the formyl compound with sodiumbisulphite, hydrogen cyanide, acetonecyanohydrin, Me₃ SiCN/KCN,hydrazines or hydroxylamines respectively.

The formyl group of compounds of Formulae (2) and (3) in which Y isformyl and of Formula (10) may also be protected as described above. Thereactions to protect the formyl group form a further feature of thepresent invention.

The 4-hydroxy group, in the the compound of Formula (1) in which Z is H,may be protected for example by reaction with a compound of formula Z--X(wherein Z is as hereinbefore defined except --H and --NO₂ and X ishalogen, especially --Cl or --Br). Compounds of Formula (1) in which Zis --NO₂ may be prepared by reaction of the corresponding compound ofFormula (1) in which Z is mesyl with a tetraalkylammonium nitrate.Further details of reactions for the preparation of --OZ compounds inwhich Z is a protecting group are described in `Protective Groups inOrganic Synthesis`, T. W. Greene and P. G. M. Wuts published by Wiley &Sons 2nd Edition (1991).

According to a further feature of the present invention there isprovided a process for the preparation of a tetrahydropyran-2-one of theFormula (1): ##STR7## by reduction of a dihydropyran-2-one of Formula(2): ##STR8## wherein: Y and Z are as hereinbefore defined.

This process may be performed by chemical reduction, where the compoundof Formula (2) preferably in a liquid medium, is reacted with hydrogenin the presence of a catalyst. The liquid medium is preferably anorganic liquid, and more preferably an alcohol, especially a loweralkanol such as ethanol, n-propanol or isopropanol or water or a mixtureof water and lower alkanol such as water/ethanol or an ester such asethylacetate or isopropylacetate. Suitable catalysts are metal catalystspreferably those where the metal is from Group VIII of the PeriodicTable. The catalyst is preferably a finely divided metal or is a metalcarried on a support such as carbon or aluminium oxide. An especiallypreferred catalyst is Raney nickel. The process is preferably performedat a temperature from 0° C. to 120° C., more preferably from 10° C. to80° C. and especially from 20° C. to 50° C. The process is convenientlycarried out at the boiling point of the liquid medium and at a pressurefrom 1×10⁴ Pa to 1× 10⁶ Pa, preferably from 5×10⁴ Pa to 5×10⁵ Pa andespecially at from 8×10⁴ Pa to 2×10⁵ Pa. The process is preferablycontinued until substantially all the starting material is consumedwhich may be detected by chromatographic analysis. The product may beisolated by removing the catalyst by filtration and evaporation of theliquid medium. The product may be purified by any convenient means suchas distillation or crystallisation.

Where dihydropyran-2-ones of Formula (2) are already optically resolvedat the 6-position chemical reduction of the double bond between the 3-and 4-positions with cis- or trans-control fixes the stereochemistry atthe 4-position and individual enantiomers can be obtained. For examplewith cis-control enantiomers of Formulae (1J) or (1K) are obtained andwith trans-control, enantiomers of Formulae (1I) or (1L) can beobtained. However, where dihydropyran-2-ones of Formula (2) are racemic,chemical reduction with no cis-trans selectivity, produces a mixture ofisomers of Formulae (1I), (1J), (1K) and (1L): ##STR9##

Separation of a mixture of isomers of Formulae (1I), (1J), (1K) and (1L)may be achieved by reacting the mixture with optically activeα-methylbenzylamine to form the corresponding diastereomericα-methylbenzylamide derivatives. The α-methylbenzylamide derivatives maybe separated by any convenient means such as chromatography orcrystallisation. After separation each α-methylbenzylamide derivative isfirstly hydrolysed and then dehydrated to reform the individual isomersof Formulae (1I) to (1L).

According to a further feature of the present invention there isprovided a process for the preparation of a dihydropyran-2-one of theFormula (2): ##STR10## by reduction of a pyran-2-one of the Formula (3):##STR11## wherein: Y and Z are as hereinbefore defined.

The process may be performed by chemical reduction, where the compoundof Formula (3) preferably in a liquid medium, is reacted with hydrogenin the presence of a catalyst. The liquid medium is preferably anorganic liquid and especially an alkanol such as ethanol, or propanol oran ester such as ethylacetate. Suitable catalysts are metal catalystspreferably where the metal is from Group VIII of the Periodic Table. Thecatalyst is preferably a finely divided metal or metal supported on acarbon or aluminium oxide support and is optionally modified bypre-treatment before use in the process. The catalyst is preferablypalladium on carbon with a metal loading of from 0.5 to 10% by weightpreferably from 1 to 5% by weight. The process is preferably performedat a temperature from 0° C. to 80° C., preferably from 15° C. to 50° C.,especially from 20° C. to 30° C. The process is preferably performed ata pressure from 1×10⁴ Pa to 1×10⁷ Pa, more preferably from 1×10⁵ Pa to1×10⁷ Pa. The process is preferably continued until all the startingmaterial is consumed. The product may be isolated by removing thecatalyst by filtration and evaporation of the liquid medium. The productmay be purified by any convenient means such as distillation orcrystallisation.

According to the present invention there is provided a process for theresolution of dihydropyran-2-ones of the Formula (2): ##STR12## whichcomprises a selective reaction of one enantiomer with a reagentcatalysed by a hydrolase enzyme whereby the enantiomer is preferentiallyconverted into a distinct chemical species from the other enantiomer sothat it is susceptible of separation by an appropriate chemical orphysical separation process, wherein Y and Z are as hereinbeforedefined.

The conditions for trans-esterification, esterification and hydrolysisreactions described above for the resolution of compounds of Formula (1)are applicable to the resolution of compounds of Formula (2); althoughthe especially preferred enzymes for the resolution of the compounds ofFormula (2) are Pseudomonas fluorescens lipases from Biocatalysts orFluka Chemie, Chromobacterium viscosum lipase from Biocatalysts, Candidacylindracae from Biocatalysts, Fluka Chemie or Sigma, Mucor Miehi fromBiocatalysts or Fluka Chemie and Lipoprotein lipase from BoehringerMannhelm or Fluka Chemie. The process may be illustrated by thefollowing schemes whereby a racemate of Formula (2) may be resolved.##STR13##

The products of these reactions may be separated by standard methodssuch as solvent extraction, chromatography or crystallisation.

According to a further feature of the present invention there isprovided a process for the preparation of a tetrahydropyran-2-one of theFormula (1): ##STR14## by reduction of a pyran-2-one of the Formula (3):##STR15## wherein: Y and Z are as hereinbefore defined.

The process may be performed by chemical reduction where the compound ofFormula (3) is reacted in a liquid medium with hydrogen in the presenceof a catalyst. The liquid medium is preferably an organic liquid andmore preferably an alkanol such as methanol, ethanol, n-propanol orn-butanol or an ester such as ethyl acetate. Alternatively, the liquidmedium may be water or a mixture of water and alkanol such aswater/ethanol. Suitable catalysts are metal catalysts preferably thosewhere the metal is from Group VIII of the Periodic Table. The catalystis preferably a finely divided metal or a metal carried on a supportsuch as carbon, more preferably Raney Nickel. The process is preferablyperformed at a temperature from 20° C. to 130° C. and more preferablyfrom 50° C. to 100° C. The process may be conveniently carried out atthe boiling point of the liquid medium.

The process is performed at a pressure from 1×10⁴ Pa to 1×10⁶ Pa,preferably from 5×10⁴ Pa to 5×10⁵ Pa and especially from 8×10⁴ Pa to2×10⁵ Pa. The process is preferably continued until substantially allthe starting material is consumed. The product is isolated by removingthe catalyst by filtration and evaporation of the liquid medium. Theproduct is purified by any convenient means such as chromatography,distillation or crystallisation.

The hydrogenation of the pyran-2-one of Formula (3) to thetetrahydropyran-2-one of Formula (1) may be carried out in two stageswithout isolation of the intermediate dihydropyan-2-one of Formula (2),the first stage in the presence of a more selective catalyst, such aspalladium on carbon and the second stage in the presence of a lessselective catalyst, such as Raney nickel.

According to a further feature of the present invention there isprovided a process for the preparation of a pyran-2-one of the Formula(3) in which Y is formyl by reaction of a pyran-2-one of the Formula(4): ##STR16## firstly with pyridine and secondly with a mixture of anitroso compound and a base, wherein:

Z is as hereinbefore defined; and

X is halogen.

The halogen represented by X is preferably --Cl, --Br, --I, morepreferably --Br.

This process may be performed by reaction of a compound of Formula (4)firstly with pyridine and secondly with a mixture of a nitroso compoundand a base in a liquid medium. The liquid medium is preferably anaqueous alkanol, more preferably aqueous ethanol. The nitroso compoundis preferably an aromatic nitroso compound such as4-nitroso-N,N-dimethylaniline. The base is preferably an inorganic basesuch as potassium carbonate. The process is preferably carried out at atemperature from -10° C. to 50° C. more preferably from 0° C. to 30° C.The process is continued until substantially all the starting materialis consumed. The intermediate "pyranyl N-oxide" is isolated byfiltration of the reaction mixture and the pyran-2-one of Formula (3) inwhich Y is formyl is liberated by acidifying with an aqueous acid suchas hydrochloric acid and extracting with an organic solvent followed byevaporation. The product is purified by chromatography as hereinbeforedescribed.

According to a further feature of the present invention there isprovided a process for the preparation of a pyran-2-one of the Formula(3) in which Y is formyl by oxidation of a pyran-2-one of the Formula(7): ##STR17## wherein: Z is as hereinbefore defined.

This process may be performed by oxidation of a compound of Formula (7)in a liquid medium with an oxidising agent. The liquid medium ispreferably an organic liquid more preferably an ether such as dioxan.The oxidising agent is preferably selenium dioxide.

The process is preferably carried out at a temperature from 125° C. to250° C. and more preferably from 160° C. to 200° C. The process ispreferably carried out under pressure in a sealed vessel.

The process is continued until substantially all the starting materialis consumed. The product is isolated by filtering the reaction mixtureto remove the residual solids followed by evaporation of the liquidmedium. The product may be purified by any convenient means such aschromatographing from a silica column using a mixture of methylenechloride/methanol as eluent.

According to a further feature of the present invention there isprovided a process for the preparation of a pyran-2-one of the Formula(4): ##STR18## by removal of a group W from a pyran-2-one of the Formula(5): ##STR19## wherein: W is --COT¹ in which T¹ is an optionallysubstituted hydrocarbon group, --CHX₂, --CH₂ X in which X is halogen;and

Z is as hereinbefore defined.

In pyran-2-ones of Formula (5) W is preferably --COC₁₋₂ -alkyl which maybe optionally substituted by halogen.

The present process may be performed by heating the pyran-2-one ofFormula (5) in a liquid medium in the presence of an acid. The acid ispreferably an inorganic acid, more preferably H₂ SO₄. The process ispreferably performed at a temperature from 50° C. to 200° C., morepreferably at from 80° C. to 150° C. and especially at from 80° C. to135° C. The process is preferably continued until all the startingmaterial is consumed. The product may be isolated by neutralising thereaction mixture and extracting with a solvent and evaporating thesolvent. The product may be purified by any convenient method such asdistillation or crystallisation.

The removal of a group W is not limited to the present pyran-2-one ofFormula (5) and may be conveniently carried out at any stage in theoverall process, i.e. if a pyran-2-one of Formula (3) or (6) belowcarries a group W in the 3-position this may be removed under similarconditions to those described above.

According to a further feature of the present invention there isprovided a process for the preparation of a pyran-2-one of the Formula(5): ##STR20## by halogenation of a pyran-2-one of the Formula (6):##STR21## wherein: W, X and Z are as hereinbefore defined.

The present process may be performed by halogenation of a pyran-2-one ofFormula (6) in a liquid medium with a halogenating agent, optionally inthe presence of ultraviolet light and optionally in the presence of anorganic peroxide to initiate the reaction.

The liquid medium is preferably an organic liquid which either does notitself undergo halogenation under the reaction conditions or which isalready full halogenated. The organic liquid is preferably a haloalkanesuch as tetrachloromethane or hexachloroethane. The halogenating agentis preferably an N-halosuccinimide such as N-chlorosuccinimide forchlorination, N-bromosuccinimide for bromination.

Where an organic peroxide is used to initiate the reaction it ispreferably an aromatic peroxide such as benzoyl peroxide or an aliphaticperoxide such as t-butyl hydroperoxide.

The process is preferably carried out at a temperature from 0° C. to100° C., preferably from 30° C. to 80° C. and more preferably from 50°C. to 80° C. The reaction is continued until substantially all thestarting material has been consumed. The product is isolated byevaporation of the liquid medium and purified by any convenient meanssuch as column chromatography.

According to a further feature of the present invention there isprovided a process for the preparation of a pyran-2-one of the Formula(8): ##STR22## by halogenation of a compound of the Formula (5):##STR23## wherein; W, X and Z are as hereinbefore defined.

This process may be performed under the conditions described above forhalogenation of a compound of Formula (6).

According to a further feature of the present invention there isprovided a process for the preparation of a pyran-2-one of Formula (3)in which Y is --CH(OR)₂ by reaction of a pyran-2-one of Formula (8) inwhich Z is as hereinbefore defined, W is --H and X is halogen with acompound ROH wherein R is as hereinbefore defined in the presence of asilver salt. X is preferably --Cl or --Br, ROH is preferably an alkanolsuch as methanol or ethanol and silver salt is preferably silvernitrate. The process is preferably carried out at a temperature from 20°C. to 100° C. and is continued until substantially all the startingmaterial is consumed. The product may be isolated by removal of thecompound ROH and may be purified by any convenient means such aschromatograhpy.

According to a further feature of the present invention there isprovided a process for the preparation of a pyran-2-one of the Formula(10): ##STR24## by hydrolysis of a compound of the Formula (8):##STR25## wherein; W, X and Z are as hereinbefore defined.

This process may be performed by hydrolysis of the compound of Formula(2) in a liquid medium. The liquid medium is preferably an alkanol suchas methanol, ethanol or isopropanol or water or a mixture of alkanol andwater. The hydrolysis may be effected in a number of ways by adding:

i) an acid, preferably an inorganic acid such as sulphuric acid orhydrochloric acid;

ii) a base preferably an inorganic base such as sodium or potassiumhydroxide;

iii) by adding as silver nitrate; or

iv) a buffer to maintain the pH at approximately 7 to the compound ofFormula (2) in the liquid medium. The process is preferably carried outat a temperature from 0° C. to 150° C. and more preferably from 50° C.to 120° C. and conveniently at the boiling point of the liquid medium.The process is continued until substantially all the starting materialis consumed. The product is isolated by neutralisation of the reactionmixture, extraction with an organic liquid, separation and evaporation.The product is purified by any convenient means such as distillation orcolumn chromatography.

According to a further feature of the present invention there isprovided a process for the preparation of a pyran-2-one of the Formula(11): ##STR26## by hydrolysis of a pyran-2-one of the Formula (5):##STR27## wherein; W, X and Z are as hereinbefore defined.

This process may be performed by hydrolysis of the compound of Formula(5) in a liquid medium.

The liquid medium is preferably an alkanol such as methanol, ethanol orisopropanol or water or a mixture of alkanol and water. The hydrolysismay be effected in a number of ways by adding:

i) an acid. preferably an inorganic acid such as sulphuric acid orhydrochloric acid:

ii) a base preferably an inorganic base such as sodium or potassiumhydroxide;

iii) by adding silver nitrate; or

iv) a buffer to maintain the pH at approximately 7 to the compound ofFormula (5) in the liquid medium. The process is preferably carried outat a temperature from 0° C. to 150° C. and more preferably from 50° C.to 120° C. and conveniently at the boiling point of the liquid medium.

The process is continued until substantially all the starting materialsare consumed. The product is isolated by neutralisation of the reactionmixture, extraction with an organic liquid, separation and evaporation.The product is purified by any convenient means such as distillation orcolumn chromatography.

According to a further feature of the present invention there isprovided a process for the preparation of a pyran-2-one of the Formula(10): ##STR28## by oxidation of a pyran-2-one of the Formula (11):##STR29## wherein: W and Z are as hereinbefore defined.

This process may be performed under the oxidation conditions describedabove for Formula (7).

According to a further feature of the present invention there isprovided a process for the preparation of a pyran-2-one of the Formula(7) by removal of a group W from a pyran-2-one of Formula (6) wherein Wand Z are as hereinbefore defined. The removal of the group W may beperformed under the conditions described above for removal of the groupW from the pyran-2-one of Formula (5).

According to a further feature of the present invention there isprovided a process for the preparation of a pyran-2-one of Formula (4)by halogenation of a pyran-2-one of Formula (7). The halogenation may beperformed under the conditions described above for halogenating thepyran-2-one of Formula (6).

Halogenation of the pyran-2-one of Formula (6) in which W is --H to givethe corresponding pyran-2-one of Formula (5) in which W is --H orhalogenation of the pyran-2-one of Formula (5) in which W is --H to givethe corresponding pyran-2-one of Formula (8) in which W is --H orhalogenation of the pyran-2-one of Formula (8) in which W is --H to givethe corresponding pyran-2-one of Formula (9) in which W is --H may beperformed under the conditions described above for halogenating thepyran-2-one of Formula (6).

Pyran-2-ones of Formula (5) where X is --I may also be prepared frompyran-2-ones of Formula (5) where X is --Br by halogen exchange in aliquid medium with iodide optionally in the presence of a phase transfercatalyst. The phase transfer catalyst is preferably a tetraalkylammonium halide such as tetrabutylammonium bromide. The liquid medium ispreferably an organic liquid, more preferably a ketone such as acetoneor methylethylketone or a lower alkanol such as ethanol or isopropanol.The iodide is preferably an inorganic iodide such as potassium or sodiumiodide. This process forms a further aspect of the present invention.

The pyran-2-one of Formula (5) in which W is --H and Z is --H may beprepared by reaction of an acid chloride of formula XCH₂ COCl withketen, followed by cyclisation of the intermediate dioxohexanoic acidchloride to the compound of Formula (5).

The pyran-2-one of Formula (5) in which W is --COCH₂ X and Z is --H maybe prepared by the self-condensation of 2 equivalents of a beta-ketoester of the formula XCH₂ COCH₂ COOEt, in which Y is as hereinbeforedefined, in a liquid medium such as chloroform in the presence ofphosphorus pentoxide, further details are provided in Izv. Akad. Nauk.SSR, Ser. Khim. (1982) 1657.

According to the a further feature of present invention there isprovided a process for the preparation of a compound of the Formula(13): ##STR30## by the elimination of ZOH from a compound of Formula(1): ##STR31## wherein: Y and Z are as hereinbefore defined.

A particular utility of the compounds of Formula (13) is that theypermit synthesis of trans isomers of compounds of Formula (1) from thecis isomers or from cis/trans mixtures, for example: ##STR32## whereinR' is any of the groups hereinbefore defined for Z or an optionallysubstituted C₁₋₁₂ -alkyl.

For compounds of Formula (1) in which Z is --H the process may beperformed by dehydrating the compound of Formula (1) in a liquid mediumin the presence of a dehydration catalyst. The liquid medium ispreferably an organic liquid, more preferably an aromatic hydrocarbonsuch as toluene or xylene. Suitable dehydration catalysts are sulphonicacids preferably aromatic sulphonic acids such as p-toluenesulphonicacid. The process is preferably performed at a temperature from 20° C.to 150° C., more preferably from 50° C. to 150° C. and especially at theboiling point of the liquid medium. The reaction is continued untilsubstantially all the starting material is consumed. After washing toremove the catalyst the product is isolated by evaporation of the liquidmedium and is purified by any convenient means such as crystallisation,solvent extraction or chromatography.

For compounds of Formula (1) in which Z is for example --SO.OR³,--(CO)OR³, --CO.R³ or --PO.(OR³)₂ the process may be performed byeliminating HOSO₂ R³, HO(CO)OR³, HOCO.R³ or HOPO.(OR³)₂ respectivelyfrom the compound of Formula (1) by reaction with a base in a liquidmedium. Suitable bases are organic nitrogen bases such as triethylamine,1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and1,5-diazabicyclo[4.3.0]non-5-ene (DBN), metal alkoxides, preferablyalkali metal alkoxides such as sodium ethoxide or potassium t-butoxideor inorganic bases such as sodium carbonate. The liquid medium ispreferably an organic liquid, more preferably a halocarbon such asdichloromethane, an aromatic hydrocarbon such as toluene or an anhydrousdipolar aprotic liquid such as dimethylformamide (DMF) anddimethylsulphoxide (DMSO). The process may optionally be performed inthe presence of a phase transfer catalyst. Suitable phase transfercatalysts are alkyl ammonium halides such as tetrabutylammonium bromideand tetramethylammonium bromide or chloride. The process is preferablyperformed at a temperature from 20° C. to 200° C., more preferably at30° C. to 100° C. The reaction is continued until substantially all thestarting material is consumed. After treatment to remove residual base,the product may be isolated by evaporation of the liquid medium andpurified as above.

Elimination of ZOH from an individual enantiomer of Formula (1) by theabove process produces a single optical isomer of Formula (13).

In compounds of Formula (1) in which Z is --H the 4-hydroxy group may beconverted to a sulphonate ester group by reaction with the correspondingsulphonyl chloride, such as 4-toluenesulphonyl chloride in the presenceof pyridine or methanesulphonyl chloride in the presence oftriethylamine.

According to a further feature of the present invention there isprovided a resolved isomer of the Formula (1) wherein Z and Y are ashereinbefore defined.

A preferred resolved tetrahydropyran-2-one isomer of Formula (1) is ofFormula (14): ##STR33## wherein: Z is --H or a protecting group; and

Y is formyl or protected formyl.

A further preferred resolved tetrahydropyran-2-one isomer of Formula (1)is of Formula (15): ##STR34## wherein: Z is --H or a protecting group;and

Y is formyl or protected formyl.

A further preferred resolved tetrahydropyran-2-one isomer of Formula (1)is of Formula (16): ##STR35## wherein: Z is --H or a protecting group;and

Y is formyl or protected formyl.

A further preferred resolved tetrahydropyran-2-one isomer of Formula (1)is of Formula (17): ##STR36## Z is --H or a protecting group; and Y isformyl or protected formyl,

except for (4S,6R) 4-hydroxy-6-di(ethylthio)methyltetrahydropyran-2-one.

According to a further feature of the present invention there isprovided a racemate comprising the compounds of Formulae (14) and (17):##STR37## wherein: Z is --H or a protecting group; and

Y formyl or protected formyl.

According to a further feature of the present invention there isprovided a racemate comprising the compounds of the Formulae (15) and(16): ##STR38## wherein:

Z is --H or a protecting group; and

Y formyl or protected formyl.

According to a further feature of the present invention there isprovided a dihydropyran-2-one of the Formula (18): ##STR39## wherein: Zis --H or a protecting group; and

Y is formyl or protected formyl.

According to a further feature of the present invention there isprovided a resolved dihydropyran-2-one of the Formula (19): ##STR40##wherein: Z is --H or a protecting group; and

Y is formyl or protected formyl.

According to a further feature of the present invention there isprovided a racemate of dihydropyran-2-ones of Formula (2) wherein Y andZ are as hereinbefore defined.

According to a further feature of the present invention there isprovided a pyran-2-one of the Formula (3) wherein Z and Y are ashereinbefore defined.

According to a further feature of the present invention there isprovided a pyran-2-one of Formula (4) wherein Z and X are ashereinbefore defined, provided that when Z is --H, X is not --Br or--Cl.

According to a further feature of the present invention there isprovided a pyran-2-one of Formula (5) wherein Z, W and X are ashereinbefore defined, provided that when Z is --H and W is --COCH₃, X isnot --Br.

According to a further feature of the present invention there isprovided a pyran-2-one of Formula (6) wherein Z and W are ashereinbefore defined, provided that when Z is --H, W is not --COCH₃.

According to a further feature of the present invention there isprovided a pyran-2-one of Formula (7) wherein Z is a protecting group.

According to a further feature of the present invention there isprovided a pyran-2-one of Formula (8) wherein Z is a protecting groupand X and W are as hereinbefore defined provided that when Z is --H andW is --COCH₃, X is not --Br.

According to a further feature of the present invention there isprovided a pyran-2-one of Formula (10) wherein Z and W are ashereinbefore defined.

According to a further feature of the present invention there isprovided a pyran-2-one of Formula (11) wherein Z and W are ashereinbefore defined, provided that when Z is --H, W is not --H or--COCH₃.

According to a further feature of the present invention there isprovided a pyran-2-one of Formula (13) wherein Y is formyl or protectedformyl.

The invention may be illustrated by the following:

EXAMPLE 1

i) 3-Acetyl-6-methyl-4-hydroxypyran-2-one may be deacylated by reactionwith 90% sulphuric acid at 130° C. to give 6-methyl-4-hydroxypyran-2-one;

ii) 6-Methyl-4-hydroxypyran-2-one may be oxidised with selenium dioxidein boiling diglyme to give 6-formyl-4-hydroxypyran-2-one;

iii) The formyl group in 6-formyl-4-hydroxypyran-2-one may be protectedby reaction with methanol in the presence of dry hydrogen chloride togive 6-dimethoxymethyl-4-hydroxypyran-2-one;

iv) 6-Dimethoxymethyl-4-hydroxypyran-2-one may be reduced in methanolwith hydrogen in the presence of a palladium on carbon catalyst to give6-dimethoxymethyl-5,6-dihydro-4-hydroxy-pyran-2-one;

v) 6-Dimethyoxymethyl-5,6-dihydro-4-hydroxypyran-2-one may be reduced inmethanol with hydrogen in the presence of a Raney nickel catalyst togive 6-dimethoxymethyl-4-hydroxytetrahydropyran-2-one;

vi) 6-Dimethoxymethyl-4-hydroxytetrahydropyran-2-one may be resolved intetrahydrofuran by transesterification with vinyl acetate in thepresence of a lipase at 40° C. according to the scheme: ##STR41## afterremoving the lipase by filtration and evaporating the volatile solventsby vacuum distillation the crude product may be chromatographed onsilica using a mixture of ethylacetate and dichloromethane to obtain the4-hydroxytetrahydropyran-2-one enantiomer represented by (A).

vii) Repeating vi) above using the trans racemate of6-dimethoxymethyl-4-hydroxytetrahydropyran-2-one produces the transisomers (A) and (C).

EXAMPLE 2

i) 6-Methyl-4-hydroxypyran-2-one as produced in Example 1 may bebrominated with N-bromosuccinimide, in carbon tetrachloride in thepresence of ultraviolet radiation to give6-dibromomethyl-4-hydroxy-pyran-2-one.

ii) 6-Dibromomethyl-4-hydroxypyran-2-one may be reacted with ethanol inthe presence of silver nitrate to give6-diethoxymethyl-4-hydroxpyran-2-one.

iii) 6-Diethoxymethyl-4-hydroxypyran-2-one may be further convertedaccording to the method of Example 1 into Compound (E): ##STR42##

EXAMPLE 3

i) 3-Acetyl-4-hydroxy-6-methylpyran-2-one may be brominated withN-bromosuccinimide in carbon tetrachloride at 40° C. in the presence ofultraviolet radiation to give 3-acetyl-6-dibromomethyl-4-hydroxypyran-2-one.

ii) 3-Acetyl-4-hydroxy-6-bromomethylpyran-2-one may be reacted withethanol in the presence of silver nitrate to give3-acetyl-6-diethoxymethyl-4-hydroxypyran-2-one.

iii) 3-Acetyl-6-diethoxymethyl-4-hydroxypyran-2-one may be reacted withaqueous acid to give 3-acetyl-6-formyl-4-hydroxypyran-2-one.

We claim:
 1. A resolved isomer of the Formula (1): ##STR43## wherein: Zis --H or a protecting group selected from the group consisting of--PO.(OR³)₂, --CO.R³, --SO.OR³, --NO₂ and --CO.OR³ in which each R³independently is optionally substituted C₁₋₁₂ -alkyl, optionallysubstituted C₂₋₁₂ -alkenyl or optionally substituted phenyl in whicheach of the alkyl and alkenyl groups represented by R³ is optionallysubstituted by C₁₋₆ -alkoxy, --Cl, --Br, --F, --OH, --CN, cyclohexyl,phenyl, --NHCOMe, --N(SiMe₃)₂ or --NR₂ in which R is --H, C₁₋₁₂ -alkyl,C₂₋₁₂ -alkenyl or phenyl and in which each of the phenyl groupsrepresented by R³ is optionally substituted by C₁₋₆ -alkyl, C₁₋₆-alkoxy, cyclohexyl, phenyl, --NO₂, --OH, --CN, --Cl, --Br, --F,--NHCOMe, --N(SiMe₃)₂ or --NR₂ ; andY is formyl or protected formylselected from the group consisting of --CH(OR)₂, --CH(SR)₂,--CH(OR)(SR), oxazolidine, imidazolidine, thiazolidine, bisulphite,cyanohydrin, hydrazone, oxime, O-acylcyanohydrin,O-tetrahydropyran-2-ylcyanohydrin, O--SiR³ cyanohydrin and ##STR44## inwhich each R independently is --H, optionally substituted C₁₋₁₂ -alkyl,optionally substituted C₂₋₁₂ -alkenyl or optionally substituted phenylin which each of the alkyl and alkyl groups is optionally substituted byC₁₋₆ -alkoxy, --Cl, --Br, --F, --OH, --CN, cyclohexyl, phenyl, --NHCOMe,--N(SiMe₃)₂ or --NR₂ in which R is selected from --H, C₁₋₁₂ -alkyl,C₂₋₁₂ -alkenyl and phenyl and in which each of the phenyl groupsrepresented by R is optionally substituted by C₁₋₆ -alkyl, C₁₋₆ -alkoxy,cyclohexyl, phenyl, --NO₂, --OH, --CN, --Cl, --Br, --F, --NHCOMe,--N(SiMe₃)₂ and --NR₂.
 2. A resolved tetrahydropyran-2-one isomer is ofFormula (14): ##STR45## wherein: Z is --H or a protecting group selectedfrom the group consisting of --PO.(OR³)₂, --CO.R³, --SO.OR³, --NO₂ and--CO.OR³ in which each R³ independently is optionally substituted C₁₋₁₂-alkyl, optionally substituted C₂₋₁₂ -alkenyl or optionally substitutedphenyl in which each of the alkyl and alkenyl groups represented by R³is optionally substituted by C₁₋₆ -alkoxy, --Cl, --Br, --F, --OH, --CN,cyclohexyl, phenyl, --NHCOMe, --N(SiMe₃)₂ or --NR₂ in which R is --H,C₁₋₁₂ -alkyl, C₂₋₁₂ -alkenyl or phenyl and in which each of the phenylgroups represented by R³ is optionally substituted by C₁₋₆ -alkyl, C₁₋₆-alkoxy, cyclohexyl, phenyl, --NO₂, --OH, --CN, --Cl, --Br, --F,--NHCOMe, --N(SiMe₃)₂ or --NR₂ ; andY is formyl or protected formylselected from the group consisting of --CH(OR)₂, --CH(SR)₂,--CH(OR)(SR), oxazolidine, imidazolidine, thiazolidine, bisulphite,cyanohydrin, hydrazone, oxime, O-acylcyanohydrin,O-tetrahydropyran-2-ylcyanohydrin, O--SiR³ cyanohydrin and ##STR46## inwhich each R independently is --H, optionally substituted C₁₋₁₂ -alkyl,optionally substituted C₂₋₁₂ -alkenyl or optionally substituted phenylin which each of the alkyl and alkyl groups is optionally substituted byC₁₋₆ -alkoxy, --Cl, --Br, --F, --OH, --CN, cyclohexyl, phenyl, --NHCOMe,--N(SiMe₃)₂ or --NR₂ in which R is selected from --H, C₁₋₁₂ -alkyl,C₂₋₁₂ -alkenyl and phenyl and in which each of the phenyl groupsrepresented by R is optionally substituted by C₁₋₆ -alkyl, C₁₋₆ -alkoxy,cyclohexyl, phenyl, --NO₂, --OH, --CN, --Cl, --Br, --F, --NHCOMe,--N(SiMe₃)₂ and --NR₂.
 3. A resolved tetrahydropyran-2-one isomer is ofFormula (15): ##STR47## wherein: Z is H or a protecting group selectedfrom the group consisting of --PO.(OR³)₂, --CO.R³, --SO.OR³, --NO₂ and--CO.OR³ in which each R³ independently is optionally substituted C₁₋₁₂-alkyl, optionally substituted C₂₋₁₂ -alkenyl or optionally substitutedphenyl in which each of the alkyl and alkenyl groups represented by R³is optionally substituted by C₁₋₆ -alkoxy, --Cl, --Br, --F, --OH, --CN,cyclohexyl, phenyl, --NHCOMe, --N(SiMe₃)₂ or --NR₂ in which R is --H,C₁₋₁₂ -alkyl, C₂₋₁₂ -alkenyl or phenyl and in which each of the phenylgroups represented by R³ is optionally substituted by C₁₋₆ -alkyl, C₁₋₆-alkoxy, cyclohexyl, phenyl, --NO₂, --OH, --CN, --Cl, --Br, --F,--NHCOMe, --N(SiMe₃)₂ or --NR₂ ; andY is formyl or protected formylselected from the group consisting of --CH(OR)₂, --CH(SR)₂,--CH(OR)(SR), oxazolidine, imidazolidine, thiazolidine, bisulphite,cyanohydrin, hydrazone, oxime, O-acylcyanohydrin,O-tetrahydropyran-2-ylcyanohydrin, O--SiR³ cyanohydrin and ##STR48## inwhich each R independently is --H, optionally substituted C₁₋₁₂ -alkyl,optionally substituted C₂₋₁₂ -alkenyl or optionally substituted phenylin which each of the alkyl and alkyl groups is optionally substituted byC₁₋₆ -alkoxy, --Cl, --Br, --F, --OH, --CN, cyclohexyl, phenyl, --NHCOMe,--N(SiMe₃)₂, or --NR₂ in which R is selected from --H, C₁₋₁₂ -alkyl,C₂₋₁₂ -alkenyl and phenyl and in which each of the phenyl groupsrepresented by R is optionally substituted by C₁₋₆ -alkyl, C₁₋₆ -alkoxy,cyclohexyl, phenyl, --NO₂, --OH, --CN, --Cl, --Br, --F, --NHCOMe,'N(SiMe₃)₂ and --NR₂.
 4. A resolved tetrahydropyran-2-one isomer is ofFormula (16): ##STR49## wherein: Z is --H or a protecting group selectedfrom the group consisting of --PO.(OR³)₂, --CO.R³, --SO.OR³, --NO₂ and--CO.OR³ in which each R³ independently is optionally substituted C₁₋₁₂-alkyl, optionally substituted C₂₋₁₂ -alkenyl or optionally substitutedphenyl in which each of the alkyl and alkenyl groups represented by R³is optionally substituted by C₁₋₆ -alkoxy, --Cl, --Br, --F, --OH, --CN,cyclohexyl, phenyl, --NHCOMe, --N(SiMe₃)₂ or --NR₂ in which R is --H,C₁₋₁₂ -alkyl, C₂₋₁₂ -alkenyl or phenyl and in which each of the phenylgroups represented by R³ is optionally substituted by C₁₋₆ -alkyl, C₁₋₆-alkoxy, cyclohexyl, phenyl, --NO₂, --OH, --CN, --Cl, --Br, --F,--NHCOMe, --N(SiMe₃)₂ or --NR₂ ; andY is formyl or protected formylselected from the group consisting of --CH(OR)₂, --CH(SR)₂, --CH(OR)(SR), oxazolidine, imidazolidine, thiazolidine, bisulphite, cyanohydrin,hydrazone, oxime, O-acylcyanohydrin, O-tetrahydropyran-2-ylcyanohydrin,O--SiR³ cyanohydrin and ##STR50## in which each R independently is --H,optionally substituted C₁₋₁₂ -alkyl, optionally substituted C₂₋₁₂-alkenyl or optionally substituted phenyl in which each of the alkyl andalkyl groups is optionally substituted by C₁₋₆ -alkoxy, --Cl, --Br, --F,--OH, --CN, cyclohexyl, phenyl, --NHCOMe, --N(SiMe₃)₂ or --NR₂ in whichR is selected from --H, C₁₋₁₂ -alkyl, C₂₋₁₂ -alkenyl and phenyl and inwhich each of the phenyl groups represented by R is optionallysubstituted by C₁₋₆ alkyl, C₁₋₆ -alkoxy, cyclohexyl, phenyl, --NO₂,--OH, --CN, --Cl, --Br, --F, --NHCOMe, --N(SiMe₂)₂ and --NR₂.
 5. Aresolved tetrahydropyran-2-one isomer is of Formula (17): ##STR51##wherein: Z is --H or a protecting group selected from the groupconsisting of --PO.(OR³)₂, --CO.R³, --SO.OR³, --NO₂ and --CO.OR³ inwhich each R³ independently is optionally substituted C₁₋₁₂ -alkyl,optionally substituted C₂₋₁₂ -alkenyl or optionally substituted phenylin which each of the alkyl and alkenyl groups represented by R³ isoptionally substituted by C₁₋₆ -alkoxy, --C₁, --Br, --F, --OH, --CN,cyclohexyl, phenyl, --NHCOMe, --N(SiMe₃)₂ or --NR₂ in which R is --H,C₁₋₁₂ -alkyl, C₂₋₁₂ -alkenyl or phenyl and in which each of the phenylgroups represented by R³ is optionally substituted by C₁₋₆ -alkyl, C₁₋₆-alkoxy, cyclohexyl, phenyl, --NO₂, --OH, --CN, --Cl, --Br, --F,--NHCOMe, --N(SiMe₃)₂ or --NR₂ ; andY is formyl or protected formylselected from the group consisting of --CH(OR)₂, --CH(SR)₂, --CH(OR)(SR), oxazolidine, imidazolidine, thiazolidine, bisulphite, cyanohydrin,hydrazone, oxime, O-acylcyanohydrin, O-tetrahydropyran-2-ylcyanohydrin,O--SiR³ cyanohydrin and ##STR52## in which each R independently is --H,optionally substituted C₁₋₁₂ -alkyl, optionally substituted C₂₋₁₂-alkenyl or optionally substituted phenyl in which each of the alkyl andalkyl groups is optionally substituted by C₁₋₆ -alkoxy, --Cl, --Br, --F,--OH, --CN, cyclohexyl, phenyl, --NHCOMe, --N(SiMe₃)₂ or --NR₂ in whichR is selected from --H, C₁₋₁₂ -alkyl, C₂₋₁₂ -alkenyl and phenyl and inwhich each of the phenyl groups represented by R is optionallysubstituted by C₁₋₆ -alkyl, C₁₋₆ -alkoxy, cyclohexyl, phenyl, --NO₂,--OH, --CN, --Cl, --Br, --F, --NHCOMe, --N(SiMe₃)₂ and --NR₂ except for(4S, 6R) 4-hydroxy-6-di(ethylthio)methyltetrahydropyran-2-one.
 6. Aracemate comprising the compounds of Formulae (14) and (17): ##STR53##wherein: Z is --H or a protecting group selected from the groupconsisting of --PO.(OR³)₂, --CO.R³, --SO.OR³, --NO₂ and --CO.OR³ inwhich each R³ independently is optionally substituted C₁₋₁₂ -alkyl,optionally substituted C₂₋₁₂ -alkenyl or optionally substituted phenylin which each of the alkyl and alkenyl groups represented by R³ isoptionally substituted by C₁₋₆ -alkoxy, --Cl, --Br, --F, --OH, --CN,cyclohexyl, phenyl, --NHCOMe, --N(SiMe₃)₂ or --NR₂ in which R is --H,C₁₋₁₂ -alkyl, C₂₋₁₂ -alkenyl or phenyl and in which each of the phenylgroups represented by R³ is optionally substituted by C₁₋₆ -alkyl, C₁₋₆-alkoxy, cyclohexyl, phenyl, --NO₂, --OH, --CN, --Cl, --Br, --F,--NHCOMe, --N(SiMe₃)₂ or --NR₂ ; andY is formyl or protected formylselected from the group consisting of --CH(OR)₂, --CH(SR)₂, --CH(OR)(SR), oxazolidine, imidazolidine, thiazolidine, bisulphite, cyanohydrin,hydrazone, oxime, O-acylcyanohydrin, O-tetrahydropyran-2-ylcyanohydrin,O--SiR³ cyanohydrin and ##STR54## in which each R independently is --H,optionally substituted C₁₋₁₂ -alkyl, optionally substituted C₂₋₁₂-alkenyl or optionally substituted phenyl in which each of the alkyl andalkyl groups is optionally substituted by C₁₋₆ -alkoxy, --Cl, --Br, --F,--OH, --CN, cyclohexyl, phenyl, --NHCOMe, --N(SiMe₃)₂ or --NR₂ in whichR is selected from --H, C₁₋₁₂ -alkyl, C₂₋₁₂ -alkenyl and phenyl and inwhich each of the phenyl groups represented by R is optionallysubstituted by C₁₋₆ -alkyl, C₁₋₆ -alkoxy, cyclohexyl, phenyl, --NO₂,--OH, --CN, --Cl, --Br, --F, --NHCOMe, --N(SiMe₃)₂ and --NR₂.
 7. Aracemate comprising the compounds of the Formulae (15) and (16):##STR55## wherein: Z is --H or a protecting group selected from thegroup consisting of --PO.(OR³)₂, --CO.R³, --SO.OR³, --NO₂ and --CO.OR³in which each R³ independently is optionally substituted C₁₋₁₂ -alkyl,optionally substituted C₂₋₁₂ -alkenyl or optionally substituted phenylin which each of the alkyl and alkenyl groups represented by R³ isoptionally substituted by C₁₋₆ -alkoxy, --Cl, --Br, --F, --OH, --CN,cyclohexyl, phenyl, --NHCOMe, --N(SiMe₃)₂ or --NR₂ in which R is --H,C₁₋₁₂ -alkyl, C₂₋₁₂ -alkenyl or phenyl and in which each of the phenylgroups represented by R³ is optionally substituted by C₁₋₆ -alkyl, C₁₋₆-alkoxy, cyclohexyl, phenyl, --NO₂, --OH, --CN, --Cl, --Br, --F,--NHCOMe, --N(SiMe₃)₂ or --NR₂ ; andY is formyl or protected formylselected from the group consisting of --CH(OR)₂, --CH(SR)₂, --CH(OR)(SR), oxazolidine, imidazolidine, thiazolidine, bisulphite, cyanohydrin,hydrazone, oxime, O-acylcyanohydrin, O-tetrahydropyran-2-ylcyanohydrin,O--SiR³ cyanohydrin and ##STR56## in which each R independently is --H,optionally substituted C₁₋₁₂ -alkyl, optionally substituted C₂₋₁₂-alkenyl or optionally substituted phenyl in which each of the alkyl andalkyl groups is optionally substituted by C₁₋₆ -alkoxy, --Cl, --Br, --F,--OH, --CN, cyclohexyl, phenyl, --NHCOMe, --N(SiMe₃)₂ or --NR₂ in whichR is selected from --H, C₁₋₁₂ -alkyl, C₂₋₁₂ -alkenyl and phenyl and inwhich each of the phenyl groups represented by R is optionallysubstituted by C₁₋₆ -alkyl, C₁₋₆ -alkoxy, cyclohexyl, phenyl, --NO₂,--OH, --CN, --Cl, --Br, --F, --NHCOMe, --N(SiMe₃)₂ and --NR₂.